Nuclear Receptor Families
Structure of Nuclear Receptors
A nuclear receptor’s structure can be broken down into four domains.
- The N-Terminal domain, or A/B domain, is the first domain, known as the hypervariable or regulatory domain. This is an incredibly disordered domain, not compliant to structural analysis.
- The DNA-binding domain (DBD), or C domain, represents the most conserved domain. The DBD contains two subdomains that each consist of four cysteine residues that organize a zinc ion to create the canonical DNA‐binding zinc finger motif.
- The flexible hinge region, or D domain, contains the carboxy-terminal extension of the DBD and acts as a link between the DBD and ligand binding domain.
- The ligand binding domain (LBD), or E/F Domain, is a complex domain that not only binds to ligands but also interacts directly with co-regulator proteins. This variability across nuclear receptors at the ligand‐binding region allows nuclear receptors to identify a diverse group of ligands.
There are 48 human nuclear receptors, several of which do not have an identified natural ligand and are considered orphan receptors. All nuclear receptors have evolutionarily-conserved sequence similarity, especially within the DNA binding domain and the ligand binding domain. The exception is a small subfamily of receptors that does not contain a DNA-binding domain (SHP-1, DAX-1), but instead bind to other nuclear receptors.